Consumer medicine information

DBL Doxorubicin Hydrochloride Injection

Doxorubicin hydrochloride

BRAND INFORMATION

Brand name

DBL Doxorubicin Hydrochloride Injection

Active ingredient

Doxorubicin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Doxorubicin Hydrochloride Injection.

What is in this leaflet

This leaflet answers some common questions about DBL™ Doxorubicin Hydrochloride Injection (doxorubicin).

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist

All medicines have risks and benefits. Your doctor or pharmacist has weighed the risks of you taking doxorubicin injection against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What DBL™ Doxorubicin Hydrochloride Injection is used for

Doxorubicin is used to treat certain cancers.

This medicine belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

Doxorubicin is thought to work by killing cancer cells, and stopping cancer cells from growing and multiplying.

Your doctor may have prescribed DBL™ Doxorubicin Hydrochloride Injection for another reason. Ask your doctor if you have any questions about why doxorubicin injection has been prescribed for you.

Doxorubicin is not addictive.

This medicine is available only with a doctor’s prescription.

Before you are given DBL™ Doxorubicin Hydrochloride Injection

When you must not be given it

You must not be given doxorubicin if you have an allergy to doxorubicin or any of the ingredients listed at the end of this leaflet

Symptoms of an allergic reaction to DBL™ Doxorubicin Hydrochloride Injection may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

You must not be given doxorubicin if you have any of the following:

  • very low white blood cell counts.
  • a very inflamed and sore mouth.
  • an infection.
  • heart problems.

You must not be given doxorubicin if you have already received the full long-term dose of doxorubicin, or other anthracyclines such as daunorubicin or epirubicin.

You must not be given doxorubicin if you are pregnant or intend to become pregnant. Doxorubicin may affect your developing baby if you are given it during pregnancy.

It is recommended that you and your doctor discuss the need for doxorubicin treatment during pregnancy, and the possible risks and benefits of using doxorubicin during pregnancy.

Doxorubicin may cause birth defects if either the male or the female is undergoing treatment at the time of conception, or if the female is receiving doxorubicin during early pregnancy. It is best to use some kind of birth control while you are receiving doxorubicin, and for at least 12 weeks after you stop receiving it. Your doctor will discuss this with you.

Many cancer medicines can cause infertility. Your doctor should discuss this issue with you before you begin therapy with doxorubicin.

You should not be given doxorubicin if you are breast-feeding or plan to breast-feed. Doxorubicin passes into breast milk. As doxorubicin may cause serious side effects in a breast-fed baby, breast-feeding is not recommended while you are receiving it.

If you are not sure whether you should be given doxorubicin, talk to your doctor or pharmacist.

Before you are given it

Tell your doctor or pharmacist if you have allergies to:

  • any other medicines
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor or pharmacist if you have or have had any medical conditions, especially the following:

  • heart problems
  • liver problems
  • a condition of the blood with a reduced number of red or white blood cells or platelets
  • lowered immunity due to treatment with medicines such as corticosteroids, cyclosporin or other medicines used to treat cancer including radiation therapy
  • lowered immunity due to diseases including HIV/AIDS.

Tell your doctor if you have an infection or high temperature. Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

Do not use doxorubicin if you have already received the full, long-term dose of doxorubicin or another anthracycline medicine.

If you have not told your doctor or pharmacist about any of the above, tell them before you are given doxorubicin.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and doxorubicin may interfere with each other. These include:

  • other medicines used to treat cancer, radiation therapy, or any other treatment which lowers your immune system
  • some medicines used to treat high blood pressure and angina (eg. propranolol, calcium channel blockers)
  • medicines for gout (eg. allopurinol, colchicine, probenecid)
  • medicines used for epilepsy (phenobarbitone or phenytoin)
  • some medicines used to treat infections (eg. clindamycin, lincamycin)
  • vaccines (ask your doctor).

These medicines may be affected by doxorubicin, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor or pharmacist will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while you are being given doxorubicin.

You should not be given any vaccinations (immunisations) without your doctor’s approval while you are being treated with doxorubicin, and for up to 12 months after you stop treatment with it. Doxorubicin may lower your body’s resistance to infection and there is a chance that you may get the infection the immunisation is meant to prevent.

In addition, other people living in your household should not take oral polio vaccine (sabin) since there is a chance they could pass the polio virus on to you.

How DBL™ Doxorubicin Hydrochloride Injection is given

How much is given

Your doctor will decide what dose will receive. This depends on your condition and other factors, such as your weight and other chemotherapy medicines you are being given.

Ask your doctor if you want to know more about the dose of doxorubicin you receive.

How it is given

Doxorubicin is usually given as a slow injection into a vein. It is sometimes injected through a rubber tube (called a catheter) into your bladder.

Doxorubicin may be given alone or in combination with other drugs.

Several courses of doxorubicin therapy may be needed depending on your response to treatment.

Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any unwanted effects have been controlled.

Doxorubicin Injection must only be given by a doctor or nurse.

How long is it given

Doxorubicin is usually given either once every 21 days, or for three consecutive days and repeated every 3 to 4 weeks.

These are called one cycle of chemotherapy. Your doctor will decide how many of these cycles you will need.

If you are given too much (overdose)

As doxorubicin is most likely to be given to you in hospital under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience any side effects after being given doxorubicin, tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital. You may need urgent medical attention.

In case of overdose, immediately contact the Poisons Information Centre for advice (telephone 13 11 26 in Australia, or call 0800 764 766 in New Zealand)

Symptoms of a doxorubicin overdose include the side effects listed below in the ‘Side Effects’ section, but are usually of a more severe nature.

While you are being given DBL™ Doxorubicin Hydrochloride Injection

Things you must do

Be sure to keep all of your doctor’s appointments so your progress can be checked. Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and detect any unwanted side effects.

Keep follow up appointments with your doctor. It is important to have follow up cycles of doxorubicin at the appropriate times to get the best effects from your treatment.

Doxorubicin can temporarily lower the number of white blood cells in your blood, increasing the chance of you getting an infection. It can also lower the number of platelets, which are necessary for proper blood clotting. If this occurs, there are certain precautions you can take, especially when your blood count is low, to reduce the risk of infection or bleeding:

  • If you can, avoid people with infections. Check with your doctor immediately if you think you are getting an infection, or if you get a fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination.
  • Check with your doctor immediately if you notice any unusual bleeding or bruising, black stools, blood in urine or stools or pinpoint red spots on your skin.
  • Be careful when using a toothbrush, dental floss or toothpick. Your doctor or nurse may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work done.
  • Do not touch your eyes or the inside of your nose unless you have just washed your hands and have not touched anything else in the meantime.
  • Be careful not to cut yourself when you are using sharp objects such as a safety razor or fingernail or toenail cutters.
  • Avoid contact sports or other situations where bruising or injury could occur.

Doxorubicin and its breakdown products may be excreted in body fluids and waste, including blood, urine, faeces, vomitus and semen.

In general, precautions to protect other people should be taken while you are receiving chemotherapy and for one week after the treatment period:

  • Flush the toilet twice to dispose of any body fluids and waste.
  • Wear gloves to clean any spill of body fluid or waste. Use paper towels or old rags, a strong solution of non-bleaching detergent and large amounts of water to mop up the spill. Discard the towels or rags into a separate waste bag and dispose of fluids in the toilet.
  • Wash linen or clothing that is heavily contaminated by body fluids or waste separately from other items. Use a strong solution of non-bleaching detergent and large amounts of water.
  • Place soiled disposable nappies and other pads in a plastic bag, seal and dispose into the garbage.
  • For sexual intercourse, use a barrier method such as a condom.

Tell your doctor, nurse or pharmacist if you have any concerns before, during or after administration of doxorubicin.

Tell your doctor or nurse immediately if you feel any pain, burning or stinging at the site of injection.

Tell any other doctors, dentists, and pharmacists who are treating you that you are being given doxorubicin.

If you are about to start on any new medicine, tell your doctor, dentist or pharmacist that you are being given doxorubicin.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are being given doxorubicin.

If you plan to be vaccinated within a year of being given doxorubicin, tell the doctor before you are vaccinated.

If you become pregnant while or soon after being given doxorubicin, tell your doctor or pharmacist immediately.

Things to be careful of

Be careful to use an effective method of contraception while you are using doxorubicin. Your doctor will tell you when it is safe to stop using contraception.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are being given doxorubicin or after the injection.

Doxorubicin helps most people with certain cancers, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects. If you are over 65 years of age you may have an increased chance of getting side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor, pharmacist or nurse if you notice any of the following and they worry you:

  • inflammation, swelling, blistering or soreness at the injection site or on the hands and feet.
  • hair loss
  • nausea and vomiting
  • burning in the mouth, throat, vagina or rectum
  • diarrhoea
  • dehydration
  • facial flushing
  • bruising
  • red coloured urine.

These are the more common side effects of doxorubicin.

Tell your doctor or nurse as soon as possible if you notice any of the following:

  • hives or skin rash
  • discolouration of nail beds and skin creases
  • drowsiness
  • conjunctivitis
  • excessive tears
  • the return of skin reactions in areas where you may have had radiation treatment previously
  • poor appetite.

These may be serious side effects. You may need medical attention.

If any of the following happen, tell your doctor or nurse immediately, or go to the Accident and Emergency department of your nearest hospital:

  • bloody or dark stools
  • chills, fever or symptoms of an infection
  • irregular heart beat.

These are very serious side effects. You may need urgent medical attention or hospitalisation.

If the doxorubicin is being injected into the bladder, tell the doctor or pharmacist if you notice any of the following:

  • stomach pain
  • blood in the urine
  • pain on passing urine
  • frequent urination

Other side effects not listed above may occur in some patients. Tell your doctor, nurse or pharmacist if you notice anything that is making you feel unwell.

Treatment with doxorubicin may cause changes in your blood cells which may be serious.

Doxorubicin may also affect how well your heart works. Your doctor will arrange regular blood tests and checks to detect any changes.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

The benefits and side effects of doxorubicin may take some time to occur. Therefore, even after you have finished your doxorubicin treatment, you should tell your doctor immediately if you notice any of the side effects listed in this section.

After being given DBL™ Doxorubicin Hydrochloride Injection

Storage

Doxorubicin Injection will be stored in the pharmacy or on the ward. The injection is kept in a refrigerator, where the temperature stays between 2 and 8°C.

After use, any unused portion of the injection will be discarded.

Product description

What it looks like

DBL™ Doxorubicin Hydrochloride Injection is a clear red liquid in a vial.

Ingredients

Active ingredient:

  • doxorubicin hydrochloride

Other ingredients:

  • sodium chloride
  • water

DBL™ Doxorubicin Hydrochloride Injection does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

DBL™ Doxorubicin Hydrochloride Injection is supplied by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

  • 10 mg/5 mL vial
    AUST R 16382
  • 50 mg/25 mL vial
    AUST R 47281

This leaflet was updated in:
September 2019

Published by MIMS December 2019

BRAND INFORMATION

Brand name

DBL Doxorubicin Hydrochloride Injection

Active ingredient

Doxorubicin hydrochloride

Schedule

S4

 

1 Name of Medicine

Doxorubicin hydrochloride.

6.7 Physicochemical Properties

Doxorubicin hydrochloride is a cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius. The chemical structure of doxorubicin consists of a tetracyclic ring, with the sugar daunosamine attached by a glycosidic linkage. Structurally, doxorubicin is related to daunomycin (daunorubicin) and differs only in hydroxyl group substitution (instead of hydrogen) at the alkyl side chain, at position '9' of the 'A' ring. It is supplied in solution form containing sodium chloride.

Chemical structure.


CAS number.

23214-92-8.

2 Qualitative and Quantitative Composition

DBL Doxorubicin Hydrochloride is available in vials containing 10 mg/5 mL and 50 mg/25 mL of the active ingredient, doxorubicin hydrochloride.

3 Pharmaceutical Form

Solution for injection.
DBL Doxorubicn Hydrochloride is a clear, red solution.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Though not completely elucidated, the mechanism of action of doxorubicin is related to its ability to bind to DNA and inhibit nucleic acid synthesis. Cell culture studies have demonstrated rapid cell penetration and perinucleolar chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, mutagenesis and chromosomal aberrations.
Doxorubicin has immunosuppressive effects. It inhibits the titre of haemolytic and haemagglutinating antibodies in mice immunised with sheep red blood cells. Similar evidence in man indicates that doxorubicin is a powerful, but temporary, immunosuppressant agent. Doxorubicin is a cell cycle, phase nonspecific cytotoxic drug.
The toxic effects of doxorubicin on the bone marrow appear to be related to its action on proliferating myeloid cells. The cardiotoxicity of doxorubicin is probably mediated by different mechanisms. Although, in animal systems, doxorubicin does inhibit DNA synthesis in cardiac muscle, it is probable that cardiotoxicity is not directly related to inhibition of cardiac muscle replication. There are some data which suggest that it is due to the generation of free radicals which damage cardiac muscle in some uncertain way. These data also suggest that concurrent administration of vitamin E and other free radical acceptors may prevent cardiotoxicity in experimental animal systems without impairing its antitumour efficacy. These studies need confirmation but they do suggest that it may be possible to divorce the antitumour effects of the drug from its cumulative cardiotoxic effects.
The specificity of doxorubicin toxicity appears to be related primarily to proliferative activity of normal tissue. Thus, the bone marrow, gastrointestinal tract and gonads are the main normal tissues damaged.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Doxorubicin is not suitable for oral administration as less than 5% of the drug is absorbed.
Pharmacokinetic studies show the intravenous administration of normal or radiolabelled doxorubicin for injection is followed by rapid plasma clearance and significant tissue binding. No information on plasma protein binding of doxorubicin is available.
The metabolism and disposition of doxorubicin is still to be defined. The drug is metabolised predominantly by the liver to doxorubicinol and several aglycone metabolites. It should be noted that several of the metabolites are cytotoxic. However, it is not certain whether any are more cytotoxic than the parent compound. High levels of metabolites appear rapidly in plasma and undergo a distribution phase with a measurable short initial half-life. Metabolism may be impaired in patients with abnormal liver function.
The disappearance of doxorubicin and its metabolites from the plasma follows a triphasic pharmacokinetic pattern with a mean half-life of the first phase of 12 minutes, of a second phase of 3.3 hours and a prolonged third phase of 29.6 hours.
Urinary excretion of doxorubicin hydrochloride and its metabolites is prolonged and accounts for only 5% of the drug excreted during the first 5 days. Approximately 50% of an administered dose is excreted in bile, and an additional 30% is excreted in bile as conjugates.
Impairment of liver function results in slower excretion and, consequently, increased retention and accumulation in plasma and tissues. Doxorubicin does not cross the blood-brain barrier.

5.3 Preclinical Safety Data

Doxorubicin and related compounds have been shown to have mutagenic and carcinogenic properties when tested in experimental models.

Genotoxicity.

Doxorubicin was genotoxic in a battery of in vitro or in vivo tests.

Carcinogenicity.

An increase in the incidence of mammary tumours was reported in rats.

4 Clinical Particulars

4.1 Therapeutic Indications

Doxorubicin has been used successfully to produce regression in neoplastic conditions such as acute leukaemia, Wilms' tumour, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, lymphomas of both Hodgkin's and non-Hodgkin's type, bronchogenic (lung) carcinoma, thyroid carcinoma, hepatomas, ovarian carcinoma etc. The main antitumour activities are listed in Table 1.
Doxorubicin is also indicated in the primary management of nonmetastatic carcinoma of the bladder (Tis, T1, T2) by intravesical administration.

4.3 Contraindications

Doxorubicin is contraindicated:
1. In patients who have marked myelosuppression or severe stomatitis induced by previous treatment with other antitumour agents or by radiotherapy.
2. In patients with impaired cardiac function. Intravenous doxorubicin should not be administered to patients with severe arrhythmias, myocardial insufficiency or myocardial infarction (see Section 4.4 Special Warnings and Precautions for Use, Cardiac toxicity).
3. In patients who have previously received the full cumulative dose of doxorubicin, daunorubicin or epirubicin.
4. In pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation): Category D. This category includes drugs which have caused, are suspected to have caused or may be expected to cause an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
5. In lactation (see Section 4.6 Fertility, Pregnancy and Lactation).
6. In patients with marked liver impairment.
7. In the presence of generalised infection.
8. In patients who are hypersensitive to doxorubicin and/or other anthracyclines or anthracenediones, or to other ingredients in the preparation.
Intravesical use of doxorubicin is contraindicated in the following cases:
1. invasive tumours which have penetrated the bladder wall;
2. urinary infections;
3. inflammation of the bladder;
4. catherisation of the bladder (e.g. due to massive intravesical tumours);
5. haematuria.
Doxorubicin should not be administered by intramuscular or subcutaneous injection, as administration by these routes will result in severe tissue necrosis.

4.4 Special Warnings and Precautions for Use

Experienced physician.

Doxorubicin should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents, and only when the potential benefits of doxorubicin therapy outweigh the possible risks. Appropriate facilities should be available for adequate management of complications should they arise.
Doxorubicin is not an antimicrobial agent.

Cardiac toxicity.

Special attention must be given to the cardiac toxicity exhibited by doxorubicin. Although uncommon, acute left ventricular failure has occurred, particularly in patients who have received total dosage of the drug exceeding the currently recommended limit of 550 mg/m2 body surface area.
For patients who have had mediastinal irradiation, concurrent high dose cyclophosphamide or hypertensive cardiomegaly, it is recommended that the cumulative total lifetime dose of doxorubicin (including related medicines such as daunorubicin and epirubicin) be less than 400 mg/m2.
Congestive heart failure and/or cardiomyopathy usually develops within two months of termination of doxorubicin therapy, but may not occur until several months to years after discontinuation of doxorubicin therapy. Delayed onset cardiomyopathy may be fatal in as many as 60% of the patients who develop it. It is more likely to occur in children or elderly patients, patients previously treated with radiotherapy to the chest, or those given relatively high single doses, infrequently. Delayed onset cardiomyopathy may appear in response to stressful situations (e.g. surgery, pregnancy), exercise (e.g. weightlifting) or acute viral infection.
Cardiac failure is often not favourably affected by presently known medical or physical therapy for cardiac support. Early clinical diagnosis of drug induced heart failure appears to be essential for successful treatment with digitalis, diuretics, low salt diet and bed rest. Severe cardiac toxicity may occur precipitously without antecedent ECG changes. Baseline ECG and periodic follow-up ECG during and immediately after, active drug therapy is an advisable precaution. Transient ECG changes, such as T-wave flattening, S-T depression and arrhythmias, are not considered indications for suspension of doxorubicin therapy. A persistent reduction in the voltage of the QRS wave is presently considered more specifically predictive for cardiac toxicity. If this occurs, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.
Measurement of the left ventricular ejection fraction using echocardiography or multigated radionuclide angiography (MUGA) is more sensitive and specific than ECG testing for evaluating and monitoring cardiac function. Endomyocardial biopsy is considered to be the most definitive test for anthracycline induced cardiotoxicity, but is invasive.
Cardiac function test methods should be employed in the following order: ECG testing, left ventricular ejection fraction, endomyocardial biopsy. If testing indicates possible myocardial toxicity, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage.
Cardiac function should be routinely assessed before doxorubicin therapy is initiated, and monitored periodically during treatment, to reduce the risk of severe cardiac impairment developing. Since functional impairment may be masked by compensatory hypertrophy, patients with previous abnormal test results should continue to be considered at risk. Left ventricular function should be evaluated before each dose of doxorubicin in excess of a cumulative anthracycline dose of 450 mg/m2.
If any additional risk factor for cardiac toxicity is present, cardiac toxicity might occur at lower cumulative doses and the monitoring of cardiac function must be particularly strict. Risk factors for cardiac toxicity include a previous history of heart disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous treatments with anthracyclines or anthracenediones, concomitant use of other cardioactive compounds (e.g. calcium channel blocking drugs) or concomitant use of other potentially cardiotoxic drugs (e.g. cyclophosphamide, 5-fluorouracil or trastuzumab). Anthracyclines including doxorubicin should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab (variable half-life; washout period up to 7 months), may also be at an increased risk of developing cardiotoxicity.

Note.

Trastuzumab emtansine has a shorter half-life of approximately 4 days. The half-life of trastuzumab is variable and may persist in the circulation for up to 7 months. Therefore, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
Doxorubicin induced cardiotoxicity mostly develops during the course of therapy up to two months from its termination but late events (several months to years after treatment termination) have occurred. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Subacute effects such as pericarditis/myocarditis have also been reported. Life threatening CHF is the most severe form of anthracycline induced cardiomyopathy and represents the cumulative dose limiting toxicity of the drug.
Patients with a history of cardiovascular disease should only be treated with doxorubicin if the benefits outweigh the risks to the patient.

Obese patients.

Systemic doxorubicin clearance tends to be decreased in obese patients; such patients must be carefully monitored if they are being treated with the maximum recommended doses of doxorubicin.

Bone marrow depression.

There is a high incidence of bone marrow depression, primarily of leucocytes, requiring careful haematological monitoring. With the recommended dosage schedule, leucopenia is usually transient, reaching its nadir at 10 to 14 days after treatment, with recovery usually occurring by the 21st day. White blood cell counts as low as 1,000/mm3 are to be expected during treatment with appropriate doses of doxorubicin. Red blood cell and platelet levels should also be monitored, since they may also be depressed. Haematologic toxicity may require dose reduction or suspension or delay of doxorubicin therapy.
When using doxorubicin as part of chemotherapy regimens which combine drugs of similar pharmacological effects (i.e. cytotoxicity) additive toxicity is likely to occur. Such additive toxicity has to be taken into consideration especially with regard to bone marrow function.
Doxorubicin is a powerful but temporary immunosuppressant agent. Appropriate measures should be taken to prevent secondary infection. Persistent severe myelosuppression may result in superinfection or haemorrhage.

Immunosuppression.

Doxorubicin is a powerful but temporary immunosuppressive agent. Appropriate measures should be taken to prevent secondary infection.
The risks and benefits should be considered before treating patients with an infection with doxorubicin, due to its immunosuppressive effects. Doxorubicin should only be administered with caution to patients with herpes zoster or with existing or recent chickenpox (including recent exposure), as there is a risk that severe generalised disease will develop.
Immunisation of patients being treated with doxorubicin should only be undertaken with extreme caution, after a careful review of the patient's haematologic status, as doxorubicin may suppress normal defence mechanisms.
Administration of live or live attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving doxorubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Concurrent use of doxorubicin with live virus vaccines may potentiate the replication of the vaccine virus, increase adverse effects of the vaccine, and/or may decrease the patient's antibody response to the vaccine. Doxorubicin may also decrease the patient's antibody response to killed virus vaccines. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on many factors; estimates vary from three months to one year.
Patients with leukemia which is in remission should not receive live virus vaccines until at least three months after their last chemotherapy treatment.
People in close contact with a patient who is being treated with doxorubicin, especially family members, should postpone immunisation with oral polio vaccines.

Severe myelosuppression.

Persistent severe myelosuppression may result in superinfection or haemorrhage.

Dental.

The bone marrow depressant effects of doxorubicin may cause an increased incidence of microbial infection, delayed healing and gingival bleeding. Patients should be instructed in proper oral hygiene during treatment, including caution in the use of toothbrushes, dental floss and toothpicks. Dental work, whenever possible, should be completed prior to initiation of therapy, or deferred until blood counts have returned to normal.

Enhanced toxicity.

It has been reported that doxorubicin may enhance the severity of the toxicity of anticancer therapies, such as cyclophosphamide induced haemorrhagic cystitis, mucositis, cardiotoxicity and bone marrow depressant effects induced by radiotherapy, and hepatotoxicity of 6-mercaptopurine.

Extravasation and rate of administration.

On intravenous administration of doxorubicin, a stinging or burning sensation signifies extravasation and, even if blood return from aspiration of the infusion needle is good, the injection or infusion should be immediately terminated and restarted in another vein. Extravasation is serious and may produce extensive local necrosis and ulceration.
The rate of administration is dependent on the size of the vein and the dosage. It is important that the dose be administered in not less than 3-4 minutes. Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration.

Tumour lysis syndrome.

Like other cytotoxic drugs, doxorubicin may induce hyperuricaemia secondary to rapid lysis of neoplastic cells (tumour lysis syndrome). The clinician should monitor the patient's blood uric acid level, potassium, calcium phosphate and creatinine, and be prepared to use such supportive and pharmacologic measures as might be necessary to control this problem. Hydration, urine alkalinisation, and prophylaxis with allopurinol to prevent hyperuricaemia may minimise potential complications of tumour lysis syndrome.

General precautions.

Initial treatment with doxorubicin requires close observation of the patient and extensive laboratory monitoring. It is strongly recommended therefore that patients be hospitalised at least during the first phase of treatment. Blood count and liver and cardiac function tests should be carried out prior to and at regular intervals during each doxorubicin treatment.
It has been reported that doxorubicin may enhance the severity of the toxicity of anticancer therapies such as: cyclophosphamide induced haemorrhagic cystitis, mucositis induced by radiotherapy, and hepatotoxicity of 6-mercaptopurine. Radiation induced toxicities (myocardium, mucosae, skin and liver) have also been reported.
As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal), have been coincidentally reported with the use of doxorubicin.
Patients should be advised that doxorubicin can discolour the urine red for one to two days after administration. This red colouring is not indicative of haematuria.
Doxorubicin should be handled with care. If the solution comes in contact with the skin or mucosa, the area should be washed thoroughly with soap and water.
Routine use of doxorubicin as adjuvant therapy in any tumour category is not recommended. The activity of doxorubicin in combination with other medicines is affected not only by the nature of the drug itself, but also by the schedule of administration.

Use in intravesical administration.

Urine cytologies and blood counts should be monitored monthly, and cytoscopic examinations should be performed at regular intervals.

Use in hepatic impairment.

Toxicity to recommended doses of doxorubicin is enhanced by hepatic impairment, therefore, prior to the individual dosing, evaluation of hepatic function is recommended using conventional clinical laboratory tests such as AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin and BSP (see Section 4.2 Dose and Method of Administration). Lower doses are recommended in these patients (see Section 4.2 Dose and Method of Administration).
Changes in hepatic function induced by concomitant therapies, either given to achieve optimal antitumour efficacy or given for the pharmacological management of concomitant diseases, may affect doxorubicin metabolism, pharmacokinetics, therapeutic efficacy or toxicity.

Use in the elderly.

Although appropriate studies with doxorubicin have not been performed in this population, cardiac toxicity may be more frequent in patients 70 years old or over. Caution should also be used in patients who have inadequate bone marrow reserves due to old age.

Paediatric use.

Doxorubicin induced cardiomyopathy impairs myocardial growth as children mature, so that paediatric patients may be at particular risk of developing delayed cardiotoxicity and, possibly, subsequent congestive heart failure during early adulthood. Periodic follow-up is therefore recommended for children who have been treated with doxorubicin.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Doxorubicin may potentiate the toxicity of other anticancer therapies.
Doxorubicin may exacerbate cyclophosphamide induced haemorrhagic cystitis, and enhance the hepatotoxicity of 6-mercaptopurine (see Section 4.4 Special Warnings and Precautions for Use, Enhanced toxicity).
Concurrent treatment with cyclophosphamide, dactinomycin or mitomycin may sensitise the heart to the cardiotoxic effects of doxorubicin. The cumulative dose of doxorubicin should be reduced in patients who have received other cardiotoxic medicines, including cyclophosphamide, mitoxantrone, idarubicin, daunorubicin or epirubicin.
A high incidence of congestive heart failure has been reported in patients who have received doxorubicin in association with paclitaxel.
Propranolol may increase the cardiotoxicity of doxorubicin as both medicines have been shown to inhibit cardiac mitochondrial coenzyme Q10.
Concurrent administration of calcium channel blockers with doxorubicin may increase the risk of cardiotoxicity.
Doxorubicin may raise the concentration of blood uric acid, secondary to rapid lysis of neoplastic cells; dosage adjustment of antigout agents (e.g. allopurinol, colchicine, probenecid, sulfinpyrazone) may be necessary to control hyperuricaemia. Serum uric acid concentrations should be monitored. Adequate oral hydration may prevent development of uric acid nephropathy. Alkalinisation of the urine may be necessary in some cases where serum uric acid concentrations are elevated.
The leucopenic, thrombocytopenic and bone marrow depressant effects of doxorubicin may be increased with concurrent or recent therapy with other medicines causing these effects. Symptoms may include severe dermatitis and/or mucositis. Dosage reduction may be required if doxorubicin is used concurrently or consecutively with other bone marrow depressants, including radiation therapy.
Doxorubicin may decrease the patient's antibody response to vaccines and/or may increase adverse effects of a live virus vaccine due to immunosuppression. This effect may persist from three months to one year (see Section 4.4 Special Warnings and Precautions for Use).
Hepatotoxic medications (e.g. high dose methotrexate, streptozocin) may impair liver function and therefore increase the toxicity of subsequently administered doxorubicin.
Phenobarbitone induces liver enzymes; therefore, concurrent administration may increase the elimination of doxorubicin. Doxorubicin may decrease serum phenytoin concentrations.
Hypersensitivity reactions to doxorubicin have been reported following recent exposure to clindamycin. The possibility of cross sensitivity between anthracyclines and clindamycin should be considered. Apparent cross sensitivity to lincomycin has also been reported.
Severe neurotoxicity, presenting as seizures and/or coma, has occurred following concurrent administration of doxorubicin and cyclosporin.
Concurrent administration of doxorubicin and cytarabine may result in colitis and necrosis (see Section 4.8 Adverse Effects (Undesirable Effects)).
Sorafenib: both increases (21-47%) and no change in the AUC of doxorubicin were observed with concomitant treatment with sorafenib 400 mg twice daily. The clinical significance of these findings is unknown.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Doxorubicin may cause infertility during the time of drug administration. In women, doxorubicin may cause amenorrhea. Although ovulation and menstruation appear to return after termination of therapy, premature menopause can occur.
Doxorubicin was toxic to male reproductive organs in animal studies, producing testicular atrophy, diffuse degeneration of the seminiferous tubules, and hypospermia A trend for delay or arrest of follicular maturation was seen in female dogs.
Doxorubicin is mutagenic and can induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent; however, sperm counts have been reported to return to normospermic levels in some instances. This may occur several years after the end of therapy. Men undergoing doxorubicin treatment should use effective contraceptive measures.
(Category D)
Doxorubicin should not be administered to pregnant women (see Section 4.3 Contraindications). Women of childbearing potential should be advised to avoid becoming pregnant while they, or their partner, are being treated with doxorubicin, and for six months following completion of doxorubicin therapy.
Doxorubicin has been reported to be embryotoxic and teratogenic in rats, and embryotoxic and abortifacient in rabbits. Studies with rabbits and rats have revealed a decreased weight gain, and a higher incidence of resorbed foetuses. Doxorubicin has been found in foetal tissue (liver, kidney and lungs) at concentrations several times that in maternal plasma, indicating that doxorubicin crosses the placenta. Dose related mutagenicity (indicated by severe chromosomal aberrations) has been reported in vitro.
Category D - This category includes drugs which have caused, are suspected to have caused or may be expected to cause an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
 Doxorubicin is distributed into milk, but limited data suggest that the amount of active drug estimated to be ingested by a breastfed infant would be small. However, because of the potential for serious adverse effects to doxorubicin in breastfed infants, breastfeeding is not recommended (see Section 4.3 Contraindications).

4.8 Adverse Effects (Undesirable Effects)

More common reactions.

Cardiovascular.

Cardiotoxicity (usually appears 1 to 6 months after initiation of therapy), i.e. cardiomyopathy, congestive heart failure. Acute life-threatening arrhythmias have been reported during or within a few hours after administration.

Dermatological.

Doxorubicin extravasation, skin necrosis, cellulitis, vesication, phlebitis, reversible complete alopecia, thrombophlebitis, lymphangitis, painful induration, erythematous streaking along the vein proximal to the site of injection, phlebosclerosis.

Gastrointestinal.

Nausea and vomiting, mucositis (stomatitis and oesophagitis), diarrhoea.

General.

Dehydration, facial flushing (if an injection has been given too rapidly).

Haematological.

Myelosuppression, leucopenia.

Other.

Red discolouration of the urine (see Section 4.4 Special Warnings and Precautions for Use).

Less common reactions.

Dermatological.

Urticarial rash, hyperpigmentation of nail beds, soles and dermal creases (primarily in children in a few cases), recall of skin reaction due to prior radiotherapy, producing erythema with vesiculisation, nonpitting oedema, severe pain, moist desquamation and palmar plantar erythrodysaesthesia.

General.

Chills and fever, generalised muscle weakness, anorexia, allergic reactions, anaphylaxis.

Haematological.

Thrombocytopenia, anaemia. The occurrence of secondary acute myeloid leukemia with or without a preleukaemic phase has been reported rarely in patients concurrently treated with DNA damaging antineoplastic agents. Such cases could have a short (1 to 3 year) latency period.

Nervous system.

Drowsiness.

Ocular.

Conjunctivitis, lacrimation.

Renal.

Renal damage, hyperuricaemia, uric acid nephropathy.

Cardiovascular.

Pericardial effusions.

Gastrointestinal.

Bleeding, ulceration, and necrosis of the colonic mucosa, which may be associated with severe and sometimes fatal infections, have occurred in patients with acute myelogenous leukaemia treated concurrently with doxorubicin and cytarabine.

Reproductive.

Amenorrhoea, azoospermia (see Section 4.6 Fertility, Pregnancy and Lactation).

Serious or life threatening reactions.

Myelosuppression.

This accompanies effective doxorubicin treatment in almost 100% of patients. Leucopenia is the predominant effect with thrombocytopenia and anaemia occurring less frequently.
Myelosuppression is more common in patients who have had extensive radiotherapy, bone infiltration by the tumour, impaired liver function (when appropriate dosage reduction has not been adopted; see Section 4.2 Dose and Method of Administration, Hepatic impairment) and simultaneous treatment with other myelosuppressive agents. The nadir (time from treatment to peripheral blood evidence of maximal myelosuppression) of leucopenia and thrombocytopenia is 10 to 15 days after treatment, and counts return to normal before day 21.

Haematological.

Secondary acute myeloid leukaemia has been reported rarely (see Less common reactions).

Mucositis.

This phenomenon is a frequent and painful complication of doxorubicin treatment but is less common than myelosuppression. Mucositis most commonly develops 5 to 10 days after treatment, and typically begins as a burning sensation in the mouth and pharynx. The mucositis may involve the vagina, rectum and oesophagus, and progress to ulceration with risk of secondary infection. The mucositis usually subsides in 10 days. Retrospective comparison of the incidence of mucositis suggests that it is less frequent as the intervals between doses increase. Mucositis may be severe in patients who have had previous irradiation to the mucosae.

Cardiotoxicity.

The cardiac abnormalities caused by doxorubicin treatment can be separated into two categories: (i) ECG alterations and (ii) congestive heart failure.
ECG changes following doxorubicin treatment occur in about 10% of patients at all dose levels of doxorubicin, are usually reversible and do not appear to be related to the subsequent development of congestive cardiac failure. The total (cumulative) dose levels of doxorubicin do correlate with the incidence of drug induced congestive cardiac failure (cardiomyopathy). Limitation of the total dose of doxorubicin to 550 or 400 mg/m2 (see Section 4.4 Special Warnings and Precautions for Use) reduces the risk of drug induced cardiomyopathy. Severe cardiotoxicity may occur months or even years after administration of doxorubicin. Delayed onset cardiotoxicity is frequently fatal (see Section 4.4 Special Warnings and Precautions for Use).
At the cellular level, doxorubicin induced cardiotoxicity is due to myocyte damage. Furthermore, as a consequence of the inhibition of cellular proliferation not only of neoplastic cells but also of normal cells, cardiac muscle cells are unable to regenerate.
Microscopic examination of endocardial biopsies shows two major types of myocyte damage:
(i) cells totally or partially devoid of myofibrillar content, even though the nucleus and mitochondria are intact;
(ii) vacuolar degeneration.
Damage to the myocardial muscle occurs with very little inflammatory reaction: muscle fibres appear to fade away. The clinical spectrum of doxorubicin toxicity ranges from subtle changes in ventricular function that can be detected only by sophisticated studies, to gross congestive cardiomyopathy with symptoms and signs of advanced congestive heart failure.
The following measures may identify patients with early doxorubicin cardiomyopathy: progressive flattening or inversion of the T-waves (mainly in the left precordial leads), low QRS voltage, prolonged systolic time interval, reduced ejection fraction (echocardiography or by cardiac pool scanning) or cardiac biopsy showing characteristic electromicroscopic changes. Doxorubicin cardiomyopathy is frequently fatal. If diagnosed early, management with digoxin, diuretics and bed rest may control heart failure.
Animal studies have indicated a possible relationship between the inhibition by doxorubicin of the mitochondrial biosynthesis of coenzyme Q10 and doxorubicin induced cardiotoxicity. Other studies have suggested that vitamin E and other free radical acceptors may prevent doxorubicin toxicity.

Intravesical use.

Systemic toxicity is not a common problem, however adverse effects have been noted at doses exceeding that recommended (see Section 4.2 Dose and Method of Administration).
Local reactions observed include chemical cystitis, contraction of the bladder, haematuria, painful micturition, frequency and urgency. These disturbances are transient.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Do not administer doxorubicin by intramuscular or subcutaneous injection (see Section 4.3 Contraindications).

Dosage.

Care in the administration of doxorubicin will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions such as urticaria and erythematous streaking. The recommended dosage schedule is 60 to 75 mg/m2 body surface area, as a single intravenous injection administered at 21 day intervals. The lower dose should be given to patients with inadequate marrow reserves due to old age, or prior therapy, or neoplastic marrow infiltration. An alternative dose schedule is 25 to 30 mg/m2 on each of three successive days, repeated every 3 to 4 weeks. (The adult dosage regimens may be suitable for paediatric cases.) The recommended lifetime cumulative dose limit is 550 mg doxorubicin hydrochloride/m2. Doxorubicin has been administered as an intra-arterial infusion for 1 to 3 days at doses of 45 to 100 mg/m2.

Paediatric.

Adult dosage regimens may be suitable for paediatric cases.
Periodic assessment of cardiac function is recommended for children who have been treated with doxorubicin, as they may be at particular risk of developing delayed cardiotoxicity (see Section 4.4 Special Warnings and Precautions for Use).

Geriatric.

It is recommended that the total cumulative dose of doxorubicin for adults aged 70 years or older be restricted to 400 mg/m2.

Method of administration.

By intravenous infusion.
It is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of 0.9% sodium chloride injection or 5% glucose injection. The tubing should be attached to a butterfly needle inserted preferably into a large vein. The rate of administration is dependent on the size of the vein and the dosage. However the dose should be administered in not less than 3 to 5 minutes.
Doxorubicin should not be mixed with heparin, dexamethasone, fluorouracil, hydrocortisone sodium succinate, aminophylline, diazepam, frusemide or cephalothin, since it has been reported that these medicines are incompatible to the extent that a precipitate may form. Doxorubicin solution may darken in colour from red to purple if mixed with fluorouracil or aminophylline. Doxorubicin is reported to be incompatible with allopurinol, cefepime and ganciclovir.
Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other medicines.
Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid administration. A burning or stinging sensation may be indicative of perivenous infiltration and the infusion should be immediately terminated and restarted in another vein.
Doxorubicin has been used in combination with other approved chemotherapeutic agents. Though evidence is available that at least in some types of neoplastic disease combination chemotherapy is superior to single agents, the benefits and risks of such therapy have not yet been fully elucidated.

Intravesical administration.

The following procedure is recommended:
1. The bladder should be catheterised and emptied.
2. Add 80 mg of doxorubicin to normal saline (final volume of 100 mL) and instil via the catheter into the bladder.
3. The catheter should be removed and the patient instructed to be on one side. At 15 minute intervals the patient should alternate to the opposite side over a 1 hour period.
4. The patient should be requested not to urinate for 1 hour, after which the bladder should be emptied of solution.
5. The procedure should be repeated at monthly intervals.

Dosage adjustments.

Renal impairment.

Doxorubicin and its metabolites are excreted in the urine to a minor degree and there are no clear indications that the pharmacokinetics or toxicity of doxorubicin are altered in patients with impaired renal function.

Hepatic impairment.

Doxorubicin is metabolised by the liver and excreted in bile. Impairment of liver function results in slower excretion of the drug and consequently increased retention and accumulation in the plasma and tissues, resulting in enhanced clinical toxicity.
Doxorubicin dosage must be reduced if hepatic function is impaired according to the following (see Table 2):

Handling precautions.

As with all antineoplastic agents, trained personnel should prepare DBL Doxorubicin Hydrochloride. This should be performed in a designated area (preferably a cytotoxic laminar flow cabinet). Protective gown, mask, gloves and appropriate eye protection should be worn when handling doxorubicin. Where solution accidentally contacts skin or mucosa, the affected area should be immediately washed, thoroughly, with soap and water. It is recommended that pregnant personnel not handle cytotoxic agents such as doxorubicin.
Luer-Lock fitting syringes are recommended. Large bore needles are recommended to minimise pressure and possible formation of aerosols. Aerosols may also be reduced by using a venting needle during preparation.
Items used to prepare DBL Doxorubicin Hydrochloride, or articles associated with body waste should be disposed of by placing in a double sealed polythene bag and incinerated at 1100°C.

4.7 Effects on Ability to Drive and Use Machines

No data available.

4.9 Overdose

Clinical features.

The symptoms of overdosage are likely to be an extension of doxorubicin's pharmacological action. Possible symptoms of toxicity are those listed (see Section 4.8 Adverse Effects (Undesirable Effects)). Some toxicity may be delayed (e.g. mucositis) or life threatening (e.g. myelosuppression and cardiotoxicity).

Management.

Symptomatic supportive measures should be instituted. Particular attention should be given to prevention and treatment of possible severe haemorrhages or infections secondary to severe, persistent bone marrow depression.

Acute animal toxicity.

The acute toxicity of doxorubicin in Swiss mice varies greatly according to the route of administration. The LD50 corresponds to 8.5 mg/kg by the intraperitoneal route, 21.1 mg/kg by the intravenous route, and is greater than 750 mg/kg by the oral route.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, water for injection.

6.2 Incompatibilities

Doxorubicin should not be mixed with heparin, dexamethasone, fluorouracil, hydrocortisone sodium succinate, aminophylline, diazepam, frusemide or cephalothin, since it has been reported that these medicines are incompatible to the extent that a precipitate may form. Doxorubicin solution may darken in colour from red to purple if mixed with fluorouracil or aminophylline. Doxorubicin is reported to be incompatible with allopurinol, cefepime and ganciclovir.
Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other medicines.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2 to 8°C. (Refrigerate. Do not freeze.) Protect from light.

6.5 Nature and Contents of Container

DBL Doxorubicin Hydrochloride 10 mg/5 mL is supplied in a pack of 1 vial.
DBL Doxorubicin Hydrochloride 50 mg/25 mL vial is supplied in a pack of 1 vial.

6.6 Special Precautions for Disposal

Spills and disposal.

If spill occurs, restrict access to the affected area. Wear two pairs of latex rubber gloves, a suitable mask, a protective gown and safety glasses. Limit the spread of the spill by covering with a suitable material such as absorbent towels or adsorbent granules. Spills may also be treated with 5% sodium hypochlorite. Collect the absorbent/adsorbent and other debris from the spill and place in a leakproof plastic container and label accordingly. Cytotoxic waste should be regarded as toxic and hazardous and clearly labelled 'Cytotoxic waste for incineration at 1100°C'. Waste material should be incinerated at 1100°C for at least 1 second. Clean the remaining spill area with copious amounts of water.

Summary Table of Changes